PROJECT SUMMARY Malaria continues to affect nearly half the world's population causing more than 500,000 deaths every year, mainly in young children. Despite recent advances, the promise of an effective vaccine still remains out of reach. Clinical trials of RTS,S, a subunit vaccine, has not been very encouraging due to a lack of protection in infants and limited, short duration protection in young children. Our proposal aims to develop a novel bioengineerable, nanoparticle (GVNP)-based malaria vaccine derived from the halophilic (salt-loving) Archaea, Halobacterium sp. NRC-1. This vaccine delivery system has unique advantages over existing platforms such as, (1) GVNPs are capable of self-adjuvanting and inducing robust immune response, (2) express and surface display complex, correctly folded foreign antigens and (3) easily scalable and extremely stable. We propose to: (a) produce and display on GVNPs 5 Plasmodium antigens that are expressed in different stages of the parasite, thereby targeting both parasite transmission and disease; (b) immunize with the antigen-displaying GVNPs and test their immunogenicity in mice; and (c) develop an efficacious combination vaccine formulation and evaluate the antibody responses against erythrocytic, pre-erythrocytic and transmission stages of malaria. These studies will lay the foundation for subsequent evaluation of the GVNP platform in the clinical setting. The development of a vaccine delivery vehicle that is safe, inexpensive, effective, and shelf-stable should lead to a revolution in the prevention of long-standing infectious diseases such as malaria.